Composition and method for treating allergic diseases

ABSTRACT

The present invention is directed towards a pharmaceutical composition useful for the treatment allergic rhinitis, asthma and related disorders. In one embodiment, the composition comprises, in combination, a therapeutically effective amount of at least one neurokinin antagonist, and a therapeutically effective amount of at least one 5-lipoxygenase inhibitor.

This application claims the Benefit of U.S. Provisional application Ser.No. 60/103,756 filed Oct. 9, 1998.

FIELD OF THE INVENTION

The present invention generally relates to compositions and methods fortreating allergic rhinitis and other respiratory diseases. Itspecifically discloses compositions which comprise (i) combinations ofantagonists of neurokinin receptors and antagonists of leukotrienereceptors, and (ii) combinations of antagonists of neurokinin receptorsand inhibitors of 5-lipoxygenase, as well as methods for treating theabove-noted diseases using such compositions.

BACKGROUND OF THE INVENTION

Neurokinin (“NK”) receptors such as the NK₁ and the NK₂ receptors arefound in the central nervous system and the circulatory system and theperipheral tissues of mammals, and are involved in a variety ofbiological processes. Antagonists of the neurokinin receptors are,therefore, expected to be useful in the treatment or prevention ofvarious mammalian diseases such as, for example, pulmonary disorderssuch as asthma, cough, bronchospasm, chronic obstructive pulmonarydiseases, and airway hyperactivity; skin disorders and itch, forexample, atopic dermatitis, and cutaneous wheal and flare; neurogenicinflammatory diseases such as, arthritis, migraine, nociception; CNSdiseases such as anxiety, emesis, Parkinson's disease, movementdisorders and psychosis; convulsive disorders, renal disorders, urinaryincontinence, ocular inflammation, inflammatory pain, and eatingdisorders such as food intake inhibition; allergic rhinitis,neurodegenerative disorders, psoriasis, Huntington's disease, depressionand various disorders such as Crohn's disease. NK, receptors have beenreported to be involved in microvascular leakage and mucus secretion,and NK₂ receptors have been associated with smooth muscle contraction,making NK₁ and NK₂ receptor antagonists especially useful in thetreatment and prevention of asthma. NK₁ and NK₂ receptor antagonistshave been reported such as, for example, in U.S. Pat. Nos. 5,798,359;5,795,894; 5,789,422; 5,783,579; 5,719,156; 5,696,267; 5,691,362;5,688,960; 5,654,316 (all assigned to Schering-Plough Corporation,Madison, N.J.); and in “Recent Advances in Neurokinin ReceptorAntagonists”, by C. J. Ohnmacht Jr., et al, Annual Reports in MedicinalChemistry, A. M. Doherty Ed., 33, 71-80 (1998).

The products of the 5-lipoxygenase (“5-LO”) pathway of arachidonic acidmetabolism, particularly the leukotrienes, can mediatebronchoconstriction, mucous secretion, airway mucosal edema, chemotaxisand mobilization of cells into the airway in the inflammatory process ofasthma. Therefore, inhibition of 5-LO should help cure, reduce orprevent such diseases. Similarly, leukotriene (“LK”) antagonists play arole in treating the multitude of symptoms associated with diseases ofthe respiratory tract, such as season allergic rhinitis, perennialallergic rhinitis, common colds, sinusitis and concomitant symptomsassociated with allergic asthma. The symptoms of such diseases mayinclude sneezing, itching runny nose, nasal congestion, redness of theeye, tearing, itching of the ears or palate, and coughs associated withpostnasal drip. A discussion of leukotriene receptors may be found in R.Robertson, Prostaglandins, 31, 395 (1986), and a discussion ofleukotriene antagonists can be found in J. Musser et al, Agents andActions, 18, 332 (1986), J. Piwinski et al, Annual Reports in MedicinalChemistry, 22, 73-76 (1987), and R. Bell et al, Annual Reports inMedicinal Chemistry, 32, 91 (1997).

It would be highly desirable to enhance the efficacy of the neurokininantagonists to improve their overall efficacy, as well as to reduce orprevent the above-noted ailments by interfering with the activity of5-LO and leukotriene receptors.

SUMMARY OF THE INVENTION

The afore-mentioned objective and other objectives and desires areaddressed by the present invention which, in one embodiment, provides acomposition for treating and preventing allergic rhinitis and otherrespiratory diseases such asthma, cough, wheezing and the like. Theinventive composition comprises, in combination, a therapeuticallyeffective amount of at least one neurokinin antagonist and atherapeutically effective amount of at least one leukotriene antagonist.One or more of the antagonists may be substituted by a pharmaceuticallyacceptable derivative such as salt, ester, and the like. Optionally, thecomposition may additionally contain a pharmaceutically acceptablecarrier, a decongestant (such as, for example, pseudoephedrine), a coughsuppressant (such as, for example, dexrtomethorphan), expectorant (suchas, for example, guaifenesin), analgesics (such as, for example,aspirin, ibuprofen and acetaminophen) or mixtures thereof.

Generally, the amount of the neurokinin antagonist content in theinventive composition per unit dosage form is about 1-1,000 milligramsand that of the leukotriene antagonist is about 2-500 milligrams.Preferably, the respective amounts are about 10-500 milligrams and about5-500 milligrams, and typically the respective amounts are about 50-200milligrams and 10-50 milligrams.

The present invention additionally provides a composition for treatingand preventing allergic rhinitis and other respiratory diseases suchasthma, cough, wheezing and the like, the composition comprising, incombination, a therapeutically effective amount of at least oneneurokinin antagonist and a therapeutically effective amount of at leastone 5-LO inhibitor. One or more of the compounds may be substituted by apharmaceutically acceptable derivative such as salt, ester, and thelike. Additionally, the composition may contain a pharmaceuticallyacceptable carrier, a decongestant, a cough suppressant, andexpectorant, or mixtures thereof.

The invention further provides methods for treating asthma, chronicobstructive pulmonary disease (“COPD”), and allergic disorders,sneezing, itching runny nose, nasal congestion, redness of the eye,tearing, itching of the ears or palate, sinusitis, and coughs associatedwith postnasal drip symptoms in a mammalian organism in need of suchtreatment comprising administering the pharmaceutical compositionsdescribed above.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention discloses pharmaceuticalcompositions that are useful in treating and preventing allergicrhinitis, asthma and related disorders. The composition comprises, incombination, a therapeutically effective amount of at least oneneurokinin antagonist and a therapeutically effective amount of at leastone leukotriene antagonist. One or more of the antagonists may besubstituted by a pharmaceutically acceptable derivative such as salt,ester, and the like.

Several neurokinin antagonists that are known currently are useful inthe practice of the present invention. Non-limiting examples of suchuseful neurokinin antagonists include, for example, those belonging tothe chemical class of oximes, hydrazones, piperidines, piperazines, arylalkyl amines, hydrazones, nitroalkanes, amides, isoxazolines,quinolines, isoquinolines, azanorbomanes, naphthyridines,benzodiazepines and the like. Many are disclosed in the U.S. patentscited earlier in this patent application. Preferred NK antagonists arethose disclosed in the above-noted U.S. Pat. Nos. 5,798,359; 5,795,894;5,789,422; 5,783,579; 5,719,156; 5,696,267; 5,691,362; 5,688,960;5,654,316. The general formula of some of so-disclosed compounds is:

wherein Z is

where

B is OR₂; NR₆COR₂, CONR₆R₇ or NR₂CONR₆R₇,

m=0 or 1,

P is R₅-aryl; or R₅-heteroaryl; and

Y is H, CR₂R₃CO₂R₆; CR₂R₃CONR₆R₇ or CR₂R₃NR₆COR₂;

a=b=0, 1 or 2;

Q has the same definitions as P above, with the proviso that P and Q maybe the same or different;

A is═N—OR₁;═N—NR₂R₃; or═CR₁R₂;

X is —O—; —NR₆—; —N(R₆)CO—; or —CO—NR₆—;

T is R₄-aryl; R₄-heteroaryl; R₄-cycloalkyl; or R₂-bridged cycloalkyl;

R₁ is H, C₁-C₆ alkyl; or (CH₂)_(n)-G where n=1-6,

G is H; R₄-aryl; R₄-heteroaryl; COR₆; CO₂R₆; CONR₆R₇; CN; OCOR₆; SO₃R₂;

C(═NOR₂)NR₆R₇; C(═NR₂)NR₆R₇, with the proviso that when n≠1, G canadditionally be OR₆, NR₆R₇ or NR₆(CO)R₇;

R₂ and R₃ are independently H or C₁-C₆ alkyl; R₄ and R₅ areindependently 1, 2 or 3 substituents independently selected from OR₂,OC(O)R₂, OC(O)NR₆R₇, C₁-C₆ alkyl, H, halogen, CF₃, C₂F₅, or OCF₃; and R₆and R₇ are independently selected from H or C₁-C₆ alkyl, with theproviso that when R₆ and R₇ are part of NR₆R₇ then said NR6R₇ may formpart of a C₅-C₆ ring wherein 0-2 ring members are selected from thegroup consisting of —O—, —S—and —NR₂—, with the further proviso thatsaid C₅-C₆ ring may contain substituents on said ring with saidsubstituents being selected from the group consisting of hydrogen,halogen, —OR₆ and —COOR₆. Particularly preferred neurokinin antagonistsare those disclosed in the above-mentioned United States patents, andbelonging to the general formula:

and stereoisomers thereof. More particularly preferred are thestereoisomers with the general formula:

where R is H; CH₂CONH₂; CH₂CONHMe; CH₂CONMe₂ or

Illustrative non-limiting examples of leukotriene antagonists useful inthe practice of the present invention include montelukast (from Merck &Company), pranlukast (from Ono Pharmaceutical Company Limited, CASRegistry Number: 103177-37-3), zafirlukast (from Zeneca Pharmaceuticals;CAS Registry Number: 107753-78-6), CP-195494 (from Pfizer,Incorporated), and the like. The technical name of montelukast is[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid. Thetechnical name of praniukast isN-[4-oxo-2-(1H-tetrazol-5yl)4H-1-benzopyran-8-yl]4-(4-phenylbutoxyybenzamide. The technical name of zafirlukast is [3-[[2-methoxy-4-[[[2-methylphenyl)sulfonyl]amino]carbonyl]phenyl]methyl]-1-methyl-1H-indol-5-yl]-carbamic acid, cyclopentylester, disclosed inEP-00199543. A particularly useful leukotriene is montelukast.Montelukast is a leukotriene D4 antagonist capable of antagonizing thereceptors for the cysteinyl leukotrienes. This compound is described inEP 480,717. A preferred pharmaceutically acceptable salt of montelukastis the monosodium salt, also known as montelukast sodium (CAS RegistryNumber: 151767-02-1).

In another embodiment, this invention discloses other pharmaceuticalcompositions that are useful in treating and preventing allergicrhinitis, asthma and related disorders. The composition comprises, incombination, a therapeutically effective amount of at least oneneurokinin antagonist and a therapeutically effective amount of at leastone inhibitor of 5-lipoxygenase. One or more of the compounds may besubstituted by a pharmaceutically acceptable derivative such as salt,ester, and the like.

Non-limiting examples of useful neurokinin antagonists are those thatare disclosed in the above-cited U.S. patents, including, for example,the compounds where R is H; CH₂CONH₂; CH₂CONHMe; CH₂CONMe₂ or

Useful 5-LO inhibitors include, for example, Zileuton (from AbbottLaboratories, CAS Registry Number: 111406-87-2) and Atreluton (fromAbbott Laboratories, CAS Registry Number: 154355-76-7). The technicalname of Zileuton is N-(1-benzo[b]thien-2-ylethyl)-N-hydroxy-urea. Thetechnical name of Atreluton isN-[(1R)-3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea.

In yet another embodiment, this invention discloses a method for thetreatment of asthma, allergic rhinitis, and other allergic disorders,sneezing, itching runny nose, nasal congestion, redness of the eye,tearing, itching of the ears or palate, wheezing, sinusitis, and coughsassociated with postnasal drip symptoms in a mammalian organism in needof such treatment comprising administering a pharmaceutical compositionwhich comprises the neurokinin antagonist and the leukotriene antagonistas described above.

In a further embodiment, the present invention teaches a method for thetreatment of asthma, allergic rhinitis, and other allergic disorders,sneezing, itching runny nose, nasal congestion, redness of the eye,tearing, itching of the ears or palate, wheezing, sinusitis, and coughsassociated with postnasal drip symptoms in a mammalian organism in needof such treatment comprising administering a pharmaceutical compositionwhich comprises the neurokinin antagonist and the 5-LO inhibitor asdescribed above.

In the pharmaceutical compositions and methods of the present invention,the active ingredients will typically be administered in admixture withsuitable pharmaceutical diluents, excipients or carriers (collectivelyreferred to herein as carrier materials) suitably selected with respectto the intended form of administration, i.e. oral tablets, capsules(either solid-filled, semi-solid filled or liquid filled), powders forconstitution, oral gels, elixirs, dispersible granules, syrups,suspensions, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of tablets or capsules, the active drug component may be combinedwith any oral non-toxic pharmaceutically acceptable inert carrier, suchas lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms)and the like. Moreover, when desired or needed, suitable binders,lubricants, disintegrating agents and coloring agents may also beincorporated in the mixture. Powders and tablets may be comprised offrom about 5 to about 95 percent inventive composition. Suitable bindersinclude starch, gelatin, natural sugars, corn sweeteners, natural andsynthetic gums such as acacia, sodium alginate, carboxymethylcellulose,polyethylene glycol and waxes. Among the lubricants there may bementioned for use in these dosage forms, boric acid, sodium benzoate,sodium acetate, sodium chloride, and the like. Disintegrants includestarch, methylcellulose, guar gum and the like. Sweetening and flavoringagents and preservatives may also be included where appropriate. Some ofthe terms noted above, namely disintegrants, diluents, lubricants,binders and the like, are discussed in more detail below.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects, i.e. neurokinin antagonism,leukotriene antagonism, 5-LO inhibition and the like. Suitable dosageforms for sustained release include layered tablets containing layers ofvarying disintegration rates or controlled release polymeric matricesimpregnated with the active components and shaped in tablet form orcapsules containing such impregnated or encapsulated porous polymericmatrices.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injections or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

Also included solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions may take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as a re conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active components, e.g., aneffective amount to achieve the desired purpose.

The quantity of the inventive active composition in a unit dose ofpreparation may be generally varied or adjusted from about 0.01milligrams to about 1,000 milligrams, preferably from about 0.01 toabout 750 milligrams, more preferably from about 0.01 to about 500milligrams, and typically from about 0.01 to about 250 milligrams,according to the particular application. The actual dosage employed maybe varied depending upon the patient's age, sex, weight and severity ofthe condition being treated. Such techniques are well known to thoseskilled in the art. Generally, the human oral dosage form containing theactive ingredients can be administered 1 or 2 times per day. The amountand frequency of the administration will be regulated according to thejudgment of the attending clinician. A generally recommended dailydosage regimen for oral administration may range from about 0.04milligrams to about 4,000 milligrams per day, in single or divideddoses.

Capsule—refers to a special container or enclosure made of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch forholding or containing compositions comprising the active ingredients.Hard shell capsules are typically made of blends of relatively high gelstrength bone and pork skin gelatins. The capsule itself may containsmall amounts of dyes, opaquing agents, plasticizers and preservatives.

Tablet—refers to a compressed or molded solid dosage form containing theactive ingredients with suitable diluents. The tablet can be prepared bycompression of mixtures or granulations obtained by wet granulation, drygranulation or by compaction.

Oral gels—refers to the active ingredients dispersed or solubilized in ahydrophillic semi-solid matrix.

Powders for constitution refers to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices.

Diluent—refers to substances that usually make up the major portion ofthe composition or dosage form. Suitable diluents include sugars such aslactose, sucrose, mannitol and sorbitol; starches derived from wheat,corn rice and potato; and celluloses such as microcrystalline cellulose.The amount of diluent in the composition can range from about 10 toabout 90% by weight of the total composition, preferably from about 25to about 75%, more preferably from about 30 to about 60% by weight, evenmore preferably from about 12 to about 60%.

Disintegrants—refers to materials added to the composition to help itbreak apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches; “cold water soluble” modified starchessuch as sodium carboxymethyl starch; natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar; cellulose derivativessuch as methylcellulose and sodium carboxymethylcellulose;microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose; alginates such as alginic acid and sodiumalginate; clays such as bentonites; and effervescent mixtures. Theamount of disintegrant in the composition can range from about 2 toabout 15% by weight of the composition, more preferably from about 4 toabout 10% by weight.

Binders—refers to substances that bind or “glue” powders together andmake them cohesive by forming granules, thus serving as the “adhesive”in the formulation. Binders add cohesive strength already available inthe diluent or bulking agent. Suitable binders include sugars such assucrose; starches derived from wheat, corn rice and potato; natural gumssuch as acacia, gelatin and tragacanth; derivatives of seaweed such asalginic acid, sodium alginate and ammonium calcium alginate; cellulosicmaterials such as methylcellulose and sodium carboxymethylcellulose andhydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics suchas magnesium aluminum silicate. The amount of binder in the compositioncan range from about 2 to about 20% by weight of the composition, morepreferably from about 3 to about 10% by weight, even more preferablyfrom about 3 to about 6% by weight.

Lubricant—refers to a substance added to the dosage form to enable thetablet, granules, etc. after it has been compressed, to release from themold or die by reducing friction or wear. Suitable lubricants includemetallic stearates such as magnesium stearate, calcium stearate orpotassium stearate; stearic acid; high melting point waxes; and watersoluble lubricants such as sodium chloride, sodium benzoate, sodiumacetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricantsare usually added at the very last step before compression, since theymust be present on the surfaces of the granules and in between them andthe parts of the tablet press. The amount of lubricant in thecomposition can range from about 0.2 to about 5% by weight of thecomposition, preferably from about 0.5 to about 2%, more preferably fromabout 0.3 to about 1.5% by weight.

Glidents—materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition, preferably from about 0.5 to about 2%by weight.

Coloring agents—excipients that provide coloration to the composition orthe dosage form. Such excipients can include food grade dyes and foodgrade dyes adsorbed onto a suitable adsorbent such as clay or aluminumoxide. The amount of the coloring agent can vary from about 0.1 to about5% by weight of the composition, preferably from about 0.1 to about 1%.

Bioavailability—refers to the rate and extent to which the active drugingredient or therapeutic moiety is absorbed into the systemiccirculation from an administered dosage form as compared to a standardor control.

Conventional methods for preparing tablets are known. Such methodsinclude dry methods such as direct compression and compression ofgranulation produced by compaction, or wet methods or other specialprocedures. Conventional methods for making other forms foradministration such as, for example, capsules, suppositories and thelike are also well known.

It will be apparent to those skilled in the art that many modifications,variations and alterations to the present disclosure, both to materialsand methods, may be practiced. Such modifications, variations andalterations are intended to be within the spirit and scope of thepresent invention.

What is claimed is:
 1. A pharmaceutical composition comprising, incombination, a therapeutically effective amount of at least oneneurokinin antagonist or a pharmaceutically acceptable derivativethereof, and a therapeutically effective amount of at least oneleukotriene antagonist or a pharmaceutically acceptable derivativethereof, wherein said neurokinin antagonist is a compound having thegeneral formula:

where B is OR₂; NR₆COR₂, CONR₆R₇ or NR₂CONR₆R₇, m=0 or 1, P is R₅-aryl;or R₅-heteroaryl; and Y is H, CR₂R₃CO₂R₆; CR₂R₃CONR₆R₇ or CR₂R₃NR₆COR₂,a═b═0, 1 or 2; Q has the same definitions as P above, with the provisothat P and Q may be the same or different; A is=N—OR₁;=N—NR₂R₃;or=CR₁R₂; X is —O—;—NR₆—;—N(R₆)CO—; or —CO—NR₆—; T is R₄-aryl;R₄-heteroaryl; R₄-cycloalkyl; or R₂-bridged cycloalkyl; R₁ is H, C₁-C₆alkyl: or (CH₂),-G where n═1-6, G is H; R₄-aryl; R₄-heteroaryl;COR₆;CO₂R₆; CONR₆R₇; CN; OCOR₆; SO₃R₂; C(═NOR₂)NR₆R₇; C(=NR₂)NR₆R₇, withthe proviso that when n≠1, G can additionally be OR₆, NR₆R₇ orNR₆(CO)R₇; R₂ and R₃ are independently H or C₁-C₆ alkyl; R₄ and R₅ areindependently 1, 2 or 3 substituents independently selected from OR₂,OC(O)R₂, OC(O)NR₆R₇, C₁-C₆ alkyl, H, halogen, CF₃, C₂F₅, or OCF₃; and R₆and R₇ are independently selected from H or C₁-C₆ alkyl, with theproviso that when R₆ and R₇ are part of NR₆R₇ then said NR₆R₇ may formpart of a C₅-C₆ ring wherein 0-2 ring members are selected from thegroup consisting of —O—, —S—and —NR₂—, with the further proviso thatsaid C₅-C₆ ring may contain substituents on said ring, with saidsubstituents being selected from the group consisting of hydrogen,halogen, —OR₆ and —COOR₆.
 2. The pharmaceutical composition of claim 1,wherein said neurokinin antagonist or its pharmaceutically acceptablederivative is present in amounts of 1-1,000 milligrams per unit dosageof said pharmaceutical composition.
 3. The pharmaceutical composition ofclaim 1, wherein said neurokinin antagonist or its pharmaceuticallyacceptable derivative is present in amounts of 10-500 milligrams perunit dosage of said pharmaceutical composition.
 4. The pharmaceuticalcomposition of claim 1, wherein said neurokinin antagonist or itspharmaceutically acceptable derivative is present in amounts of 50-200milligrams per unit dosage of said pharmaceutical composition.
 5. Thepharmaceutical composition of claim 1, wherein said leukotrieneantagonist or its pharmaceutically acceptable derivative is present inamounts of 2-500 milligrams per unit dosage of said pharmaceuticalcomposition.
 6. The pharmaceutical composition of claim 1, wherein saidleukotriene antagonist or its pharmaceutically acceptable derivative ispresent in amounts of 5-100 milligrams per unit dosage of saidpharmaceutical composition.
 7. The pharmaceutical composition of claim1, wherein said leukotriene antagonist or its pharmaceuticallyacceptable derivative is present in amounts of 10-50 milligrams per unitdosage of said pharmaceutical composition.
 8. The pharmaceuticalcomposition of claim 1, wherein said neurokinin antagonist is a compoundhaving the general formula:

and stereoisomers thereof, where R═H; CH₂CONH₂; CH₂CONHMe; CH₂CONMe₂ or


9. The pharmaceutical composition of claim 1, wherein said neurokininantagonist is a compound having the general formula:

where R is H; CH₂CONH₂; CH₂CONHMe; CH₂CONMe₂ or


10. The pharmaceutical composition of claim 9, wherein said neurokininantagonist is the compound where R is CH₂CONH₂.
 11. The pharmaceuticalcomposition of claim 9, wherein said neurokinin antagonist is thecompound where R is CH₂CONHMe.
 12. The pharmaceutical composition ofclaim 11, wherein said leukotriene antagonist is selected from the groupconsisting of montelukast, montelukast sodium, pranlukast, zafirlukastand CP-195494.
 13. The pharmaceutical composition of claim 12, whereinsaid leukotriene antagonist is montelukast sodium.
 14. Thepharmaceutical composition of claim 1, additionally containing one ormore materials selected from the group consisting of a pharmaceuticallyacceptable carrier, a decongestant, a cough suppressant and anexpectorant.
 15. A method for the treatment of asthma, allergicrhinitis, chronic obstructive pulmonary disease, sneezing, itching runnynose, nasal congestion, redness of the eye, tearing, itching of the earsor palate, wheezing, coughs associated with postnasal drip symptoms andrespiratory disorders associated with allergy in a mammalian organism inneed of such treatment, said treatment comprising: administering apharmaceutical composition comprising, in combination, a therapeuticallyeffective amount of at least one neurokinin antagonist or apharmaceutically acceptable derivative thereof and a therapeuticallyeffective amount of at least one leukotriene antagonist or apharmaceutically acceptable derivative thereof, wherein said neurokininantagonist is a compound stated in claim 1.